Tryptase inhibitors

Details Tryptase inhibitors Tryptase inhibitors

2002-09-09

2004-11-09

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S026000, C544S357000, C514S483000, C514S255030

Reexamination Certificate

active

06815557

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel tryptase inhibitors which are used in the pharmaceutical industry for preparing medicaments.
KNOWN TECHNICAL BACKGROUND
The international applications WO95/32945, WO96/09297, WO98/04537, WO99/12918, WO99/24395, WO99/24407 and WO99/40073 describe low-molecular-weight bivalent compounds for use as tryptase inhibitors.
DESCRIPTION OF THE INVENTION
It has now been found that the compounds of the formula I, which are described in more detail below, have surprising and particularly advantageous properties.
The invention provides compounds of the formula I
in which
M is a central building block of the formula below
—U1&Brketopenst;C≡C&Brketclosest;
n
U2—
n is 1 or 2,
U1 and U2 are identical or different and are methylene [—CH
2
—], ethylene [—CH
2
—CH
2
—], trimethylene [—CH
2
—CH
2
—CH
2
—], tetramethylene [—CH
2
—CH
2
—CH
2
—CH
2
—] or isopropylidene [—C(CH
3
)
2
—],
A1 is —O—B1—A3—, —A5—B1—O—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
A2 is —O—B2—A4—, —A6—B2—O—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
A3 and A4 are identical or different and are —C(O)—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
A5 and A6 are identical or different and are —C(O)—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
B1 and B2 are identical or different and are 1-4C-alkylene,
K1 is —B3—X1, —B3—Y1 or —B3—Z1—B5—X1,
K2 is —B4—X2, —B4—Y2 or —B4—Z2—B6—X2,
B3 and B4 are identical or different and are a bond or 1-4C-alkylene,
B5 and B6 are identical or different and are a bond or 1-2C-alkylene,
X1 and X2 are identical or different and are amino, aminocarbonyl or amidino,
Y1 and Y2 are imidazol-1-yl,
Z1 and Z2 are identical or different and are 5,2-pyridinylene, 6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene, 3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene,
and where on the direct route between the terminal nitrogen atoms 20 to 35, preferably 24 to 29, bonds have to be present, the salts of these compounds, and the N-oxides of the nitrogen-containing heteroaryls, heteroarylenes and heterocycloalkylenes, and their salts, where all those compounds are excluded in which one or more of the variables B3, B4, B5 or B6 adopts the meaning of a bond and there would consequently be a direct linkage of two heteroatoms.
1-4C-alkylene represents straight-chain or branched 1-4C-alkylene radicals, for example the methylene [—CH
2
—], ethylene [—CH
2
—CH
2
—], trimethylene [—CH
2
—CH
2
—CH
2
—], tetramethylene [—CH
2
—CH
2
—CH
2
—CH
2
—], 1,2-dimethylethylene [—CH(CH
3
)—CH(CH
3
)—], 1,1-dimethylethylene [—C(CH
3
)
2
—CH
2
—], 2,2-dimethylethylene [—CH
2
—C(CH
3
)
2
—], isopropylidene [—C(CH
3
)
2
—] or the 1-methylethylene [—CH(CH
3
)—CH
2
—] radicals.
By definition, the groups Z1 and Z2 are located between groups B3 and B5 (—B3—Z1—B5—) and B4 and B6 (—B4—Z2—B6—), respectively. Accordingly, in the divalent groupings mentioned by way of example (for example 3,6-indolylene), the first number indicates the point of attachment to the group B3 and B4, respectively, and the second number indicates the point of attachment to the group B5 and B6, respectively.
In the context of this application, the term “terminal nitrogen atom” means in each case a nitrogen atom in the groups designated X1, X2, Y1 and Y2.
If the group X1 or X2 contains only one nitrogen atom, this nitrogen atom is the terminal nitrogen atom.
If the group X1 or X2 contains a plurality of nitrogen atoms, the nitrogen atom which is furthest from the atom by means of which the bond to the group B3 (B5) or B4 (B6) is established is the terminal nitrogen atom.
If the group Y1 or Y2 contains only one ring nitrogen atom, this ring nitrogen atom is the terminal nitrogen atom.
If the group Y1 or Y2 contains a plurality of ring nitrogen atoms, the ring nitrogen atom which is furthest from the atom by means of which the bond to the group B3 or B4 is established is the terminal nitrogen atom.
According to the invention, the direct route between the nitrogen atoms which act as terminal nitrogen atoms in the groups defined as X1 (Y1) or X2 (Y2) is considered to be the number of bonds which is obtained by counting the bonds which represent the shortest possible connection between the terminal nitrogen atoms.
The following example is meant to illustrate the determination of the number of bonds on the direct route between two terminal nitrogen atoms:
Here, the direct route comprises 23 bonds.
Preference is given to those compounds of the formula I whose molecular weight is below 600 g/mol.
Particular preference is given to those compounds of the formula I whose molecular weight is below 500 g/mol.
Suitable salts for compounds of the formula I are all acid addition salts. Particular mention may be made of the pharmaceutically acceptable salts of inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the salts are employed in salt preparation—depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically unacceptable salts which can be obtained initially as process products, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention, and also their salts, may contain varying amounts of solvents, for example when they are isolated in crystalline form. The invention therefore also embraces all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
Compounds of the formula I which are to be emphasized are those in which
M is a central building block of the formula below
—U1&Brketopenst;C≡C&Brketclosest;
n
U2—
n is 1 or 2,
U1 and U2 are identical or different and are methylene [—CH
2
—], ethylene [—CH
2
—CH
2
—], trimethylene [—CH
2
—CH
2
—CH
2
—], tetramethylene [—CH
2
—CH
2
—CH
2
—CH
2
—] or isopropylidene [—C(CH
3
)
2
—],
A1 is —O—B1—A3—, —A5—B1—O—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
A2 is —O—B2—A4—, —A6—B2—O—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
A3 and A4 are identical or different and are —C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
A5 and A6 are identical or different and are —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,
B1 and B2 are identical or different and are 1-2C-alkylene,
K1 is —B3—Z1—B5—X1,
K2 is —B4—Z2—B6—X2,
B3 and B4 are identical or different and are a bond or 1-2C-alkylene,
B5 and B6 are identical or different and are a bond or 1-2C-alkylene,
X1 and X2 are identical or different and are amino or amidino,
Z1 and Z2 are identical or different and are 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene,
and where on the direct route between the terminal nitrogen atoms 20 to 35, preferably 24 to 29, bonds have to be present,
and the salts of these compounds.
Compounds of the formula I which are to be particu

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